The discovery and development of small molecule therapeutics for disorders of the Central Nervous System (CNS), particularly for neurodegenerative diseases, is one of the major challenges of modern biomedical research. Although great advances have been made in understanding the biological basis of neurological disorders, this scientific progress has not yet been translated into effective new treatments for these devastating disorders. This application proposes to exploit recently developed disease models in the fruit fly Drosophila melanogaster to develop a new and innovative method of small molecule drug discovery that is articularly well suited for CNS diseases. We propose to use automated procedures to screen well-validated disease models of two trinucleotide repeat disorders, Huntington's disease and spinocerebellar ataxia type I, for compounds that improve motor function. In Phase I of this project, we will use an automated screening system to develop and validate disease-specific assays, and establish by proof-of-principle experiments that the system can provide high-throughput assays that are rapid, reproducible, and highly sensitive to improved motor function in the two disease models. In Phase II, we will use this system to carry out a moderately large-scale screen (12,000 compounds) against both disorders and will begin a characterization of the "hits" that we obtain in both Drosophila and mouse disease models. The proposed project has two important outcomes. The first is to validate a method of drug discovery by in vivo screening of disease models that can be used not only for further screening for these two diseases, but also as a more general method for neurological and behavioral disorders. The second is the discovery of new bioactive compounds that can ameliorate these diseases in Drosophila, and are thus suitable lead candidates for further preclinical and clinical development in mammals, and ultimately in humans.